Laminin receptors and signals in Schwann cells

描述（由申请人提供）：层粘连蛋白对周围神经发育和髓鞘形成很重要。层粘连蛋白突变引起人类（先天性肌营养不良症，CMD）和小鼠（营养不良症，dy）的髓鞘异常神经病变，表现为雪旺细胞-轴突相互作用受损和髓鞘形成改变。在雪旺细胞中介导层粘连蛋白作用的分子，以及层粘连蛋白突变的病理机制在很大程度上仍然未知。我们已经在髓磷脂形成的雪旺细胞中发现了几种层粘连蛋白受体，并表明它们在周围神经发育过程中表达差异，表明它们起着不同的作用。我们的初步遗传分析证实了这一观点：β 1整合素是在出生之前建立适当的雪旺细胞-轴突关系所必需的，而糖代谢障碍是出生后正常髓鞘形成所必需的。在雪旺细胞中，β 1和无糖糖的形态表型表明，这些受体通常将层粘连蛋白与细胞骨架重排联系起来。这一建议的总体目标是扩大什么是已知的雪旺细胞层粘连蛋白-细胞骨架连锁的分子基础。

DESCRIPTION (provided by applicant): Laminin is important for peripheral nerve development and myelination. Laminin mutants cause a dysmyelinating neuropathy in man (congenital muscular dystrophy, CMD) and mouse (dystrophic, dy) that manifests both impaired Schwann cell-axon interactions and altered myelination. The molecules that transduce laminin effects in Schwann cells, and the pathomechanisms of laminin mutants remain largely unknown. We have identified several laminin receptors in myelin-forming Schwann cells and shown that they are differentially expressed across peripheral nerve development, suggesting that they subserve differential roles. Our preliminary genetic analysis confirms this notion: Beta1integrin is required for establishing proper Schwann cell-axon relationships prior to birth, whereas dystroglycan is necessary for normal myelination after birth. The Beta1and dystroglycan-null morphological phenotypes suggest that these receptors normally link laminin to cytoskeletal rearrangements in Schwann cells. The overall goal of this proposal is to expand what is known of the molecular basis of laminin-cytoskeletal linkage in Schwann cells. We have produced or collected an unique group of conditional alleles and Cre transgenes that will allow us to disrupt singly or multiply all known major laminin receptors in Schwann cells of transgenic mice. Furthermore, imaging and biochemical analysis of Beta1integrin-null Schwann cells will elucidate how Beta1 directs cytoskeletal rearrangements. Proteomic analysis of Beta1integrin-null Schwann cell/neuron explants will identify candidate signal molecules that link laminin to the cytoskeletal alterations required for axonal interactions. This comprehensive approach will establish the role of the different laminin receptors in peripheral nerve, thereby clarifying the pathogenesis of CMD and dy mutations. The information produced by these experiments will collectively form a basis for developing treatment strategies of CMD and other hereditary neuropathies, and to promote nerve regeneration and remyelination in all neuropathies.